An efficient and economic asymmetric synthesis of (+)-nootkatone, tetrahydronootkatone, and derivatives

Article abstract of DOI:10.1021/ol8023709

Image Persented A facile route to enantiomerically pure (+)-nootkatone and derivatives has been established through conjunctive stereoselective Grignard/anionic oxy-Cope (AOC) reactions.

Full text of DOI:10.1021/ol8023709

ORGANIC
LETTERS
2009
Vol. 11, No. 16
3530-3533
An Efficient and Economic Asymmetric
Synthesis of (+)-Nootkatone,
Tetrahydronootkatone, and Derivatives
Anne M. Sauer,† William E. Crowe,† Gregg Henderson,‡ and Roger A. Laine*,†,§
Department of Chemistry, Department of Entomology, Louisiana State UniVersity
Agricultural Center, and Department of Biological Sciences, Louisiana State
UniVersity, Baton Rouge, Louisiana 70803
rogerlaine@gmail.com
Received May 12, 2009
ABSTRACT
A facile route to enantiomerically pure (+)-nootkatone and derivatives has been established through conjunctive stereoselective Grignard/
anionic oxy-Cope (AOC) reactions.
There is a constant need for new products and applications
that possess suitable termite activity without adverse health
and environmental effects.1 It has been well documented that
highly active compounds exuded by some plants are vital to
the plants’ survival and perseverance in their natural habitat
in the face of predation. Therefore, in an effort to implement
Nature’s successful remedies for our own practicality, the
introduction of natural active compounds into “modern”
Figure 1. Valencane skeletal framework.
termiticide formulations has received growing interest and
attention in recent years. Although several botanical termiti-
cides have been identified, only pyrethrins, to date, are
available for commercial use.
(+)-Nootkatone 1 (Figure 1), first isolated from the
heartwood of Alaskan yellow cedar, Chamaecyparis noot-
katensis (D. Don),2 was later isolated from the peel of Citrus
paradisi Macfaden3 and found to be the carrier of the
grapefruit essence. In addition to its applications in the flavor
and fragrance arenas, Zhu et al. recently discovered that (+)-
nootkatone also possessed marked repellent and toxic activity
toward the devastating Formosan subterranean termite.4,5
However, the current cost affiliated with the natural product
renders it impractical for any industrial application except
† Department of Chemistry.
‡ Department of Entomology.
§ Department of Biological Sciences.
(1) Teranishi, R.; Kint, S. Bioctive Volatile Compounds from Plants:
An Overview. In BioactiVe Volatile Compounds from Plants; Teranishi,
R., Buttery, R. G., Sugisawa, H., Eds.; ACS Symposium Series 525;
American Chemical Society: Washington, DC, 1993; pp 1-5.
(2) Erdtman, H.; Hirose, Y. Acta Chem. Scand. 1962, 16, 1311.
(3) MacLeod, W. D., Jr.; Buigues, N. M. J. Food. Sci. 1964, 29, 565.
10.1021/ol8023709 CCC: $40.75
Published on Web 07/24/2009
 2009 American Chemical Society

flavors and fragrances. Also, although several research groups
have synthesized compounds from the valencane family,
none have been able to produce an economically viable
scheme that would be appropriate for large-scale production.
Therefore, it was our purpose to develop an efficient and
economic asymmetric synthesis for (+)-nootkatone and
analogues that could be applied to an industrial setting and
utilized not only for termite (and other arthropods) control
but also as a grapefruit flavor and fragrance additive.
Most synthetic approaches to the valencane skeletal
framework (Figure 1)6 have relied on Robinson annulation
reactions. However, stereospecific establishment of the
vicinal cis-dimethyl substituents and their relative configu-
ration to the isopropenyl group has proven problematic.7
In 1980, Yoshikoshi described a method for the enanti-
oselective synthesis of (+)-nookatone based on the acid-
mediated, tandem, cyclobutane cleavage-aldol cyclization
reaction sequence depicted in Scheme 1. With such an
stereocenter, and the strong steric bias imparted by the gem-
dimethyl bridge allows for highly stereocontrolled access to
the quaternary stereocenter C4a. Controlling the remaining
stereocenter C4, which is exocyclic to the pinene-derived six-
membered ring, has proved problematic, however. In Yoshi-
koshi’s published route, the relevant stereoselective step,
titanium tetrachloride catalyzed conjugate addition of allyl-
trimethylsilane to pinene-derived enone 3, provided an
inseparable diastereomeric mixture of products in a 4:1 ratio,
leaving room for improvement.8
We reasoned that the olefinic precursor B to Yoshikoshi’s
diketone A could be prepared in a stereospecific manner from
alkoxide D by sequential anionic oxy-Cope rearrangement
followed by alkylation with methyl iodide (Scheme 2).
Scheme 2. Solving the C4 Stereocenter Problem
Scheme 1. Yoshikoshi Route: the C4 Stereocenter Problem
In lieu of nopinone, inexpensive natural product ꢀ-pinene
2, a GRAS (generally recognized as safe) compound, was
chosen as the starting material for economical and environ-
mental reasons. Although the conversion of ꢀ-pinene to
nopinone could be performed via ozonolysis methods, a safer
alternative was preferred. Implementing Lee’s methodology,9
the oxidative cleavage of ꢀ-pinene was performed with mild
reaction conditions and inexpensive reagents to provide
nopinone in excellent yields (Scheme 3).
Following Yoshikoshi’s procedure, nopinone was con-
verted to the mixed aldol product 3.8 The resulting ketone
was then subjected to Grignard reagents to provide the
tertiary alcohol product 4 in excellent yields and selectivity
(>20:1).
The AOC rearrangement of 4 was found to be extremely
sensitive to reaction conditions, and some optimization
was required to obtain acceptable yields (Scheme 4). When
the AOC rearrangement was run at room temperature, an
unusual fragmentation took place leading to the loss of
the allyl or methallyl unit introduced in the previous
Grignard addition step. Although not typical, this frag-
mentation is not without precedent, and has been proposed
to proceed by a retro-ene mechanism.10 Undesired frag-
effective method for construction of the required ring system,
the problem of nootkatone synthesis is reduced to the
stereocontrolled synthesis of the diketone precursor A. Using
(-)-ꢀ-pinene as a starting material directly provides the C6
(4) In the USA, one Formosan subterranean termite colony, comprising
up to 10 million individuals, is capable of consuming a thousand pounds
of wood per year. The estimated nationwide damage reaches an excess of
$1billion dollars. In Louisiana, the damage caused by this species is valued
at $500 million; New Orleans, alone, accounts for $300 million. Henderson,
G.; Laine, R.; Zhu, B.; Ibrahim, S.; Crowe, W.; Sauer, A. Structure ActiVity
of Natural Pharmacophores Against Formosan Subterranean Termites;
American Chemical Society National Meeting, New Orleans, LA, March
23-27, 2003.
(5) (a) Zhu, B. C. R.; Henderson, G.; Chen, F.; Maistrello, L.; Laine,
R. A. J. Chem. Ecol. 2001, 27, 523–531. (b) Zhu, B. C. R.; Henderson, G.;
Sauer, A. M.; Yu, Y.; Crowe, W. E.; Laine, R. A. J. Chem. Ecol. 2003, 29,
2695–2701.
(6) The definition of the valencane skeleton is used in accord with
Marshall, J. A.; Warne, T. M. J. Org. Chem. 1971, 36, 178–183.
(7) (a) Thomas, A. F. Pure Appl. Chem. 1990, 62, 1369–1372. (b)
Inokuchi, T.; Asanuma, G.; Torii, S. J. Org. Chem. 1982, 47, 4622–4626.
(c) Hiyama, T.; Shinoda, M.; Nozaki, H. Tetrahedron Lett. 1979, 37, 3529–
3532, references therein. (d) van der Gen, A.; van der Linde, L. M.;
Witteveen, J. G.; Boelens, H. Recl. TraV. Chim. Pays-Bas 1971, 90, 1034–
1054. (e) Bessie`re, Y.; Barthe´le´my, M.; Thomas, A. F.; Pickenhagen, W.;
Starkemann, C. NouV. J. Chim 1978, 2, 365–371.
(8) Yoshikoshi, A.; Yanami, T.; Miyashita, M. J. Org. Chem. 1980, 45,
607–612.
(9) Lee, D. G.; Chen, T.; Wang, Z. J. Org. Chem. 1993, 58, 2918–
2919.
Org. Lett., Vol. 11, No. 16, 2009
3531

Subsequent Wacker oxidation (b, R ) H) or oxidative
cleavage (a, R ) Me) of 6 produces a diketone, a known
intermediate in Yoshikoshi’s route. In a chemical engineering
scale-up, this oxidation step may need to be replaced to lower
the expense and eliminate Hg byproduct. The remaining steps
in Yoshikoshi’s synthesis, concurrent cyclobutane cleavage
and aldol cyclization with subsequent dehydrochlorination,
were then interdigitated to provide an efficient and economic
asymmetric synthesis of (+)-nootkatone 1. However, to
optimize yields, an alternative procedure for the dehydro-
halogenation of the chloro enone was employed in lieu of
Yoshikoshi’s alumina prep. (+)-Nootkatone was thus pre-
pared from its hydrochloride precursor utilizing the meth-
odologies previously described by Caine.11 This modification
ultimately resulted in a 21% yield increase in the last step
of the reaction sequence.
Scheme 3. Synthetic Route to (+)-Nootkatone 1
In summation, the combination of the Grignard reaction
and the anionic Oxy-Cope rearrangement resulted in an
effective scheme to selectively generate two adjacent
stereocenters, thereby providing a synthetic sequence to
enantiomerically pure (+)-nootkatone. The overall yields
for the eight-step syntheses were 31% (R ) H) and 33%
(R ) Me), respectively. This route should be useful for a
variety of industrial applications. Not only has (+)-
nootkatone been shown effective for insects (termites,
ticks, cockroaches, mole crickets, nematodes, ectopara-
sites, and red imported fire ants), but also for termite
control with applications in wood preservatives.12 (+)-
Nootkatone synthesized also possesses substantial value
in the flavor and fragrance world.
mentation could be avoided by lowering the reaction
temperature to 0 °C. Our original plan was to treat the
enolate intermediate generated in the AOC rearrangement
with methyl iodide, thus converting 4 to 6 in one step.
However, this plan was thwarted by the unexpected
tendency of these enolates to undergo exclusively O-
alkylation instead of the desired C-alkylation. An attempt
to induce selectivity for C-alkylation by counterion
exchange (LiBr) was partially successful, but the product
yield was unacceptably low. In the end we decided to
isolate ketone 5 (aqueous quench) and then introduce the
methyl group in a subsequent step employing reaction
conditions (NaNH2, benzene, 45 °C) previously described
by Yoshikoshi.
Furthermore, tetrahydronootkatone (THN) 7 and 11,12-
dihydronootkatone 8 are two hydrogenation products of (+)-
nootkatone (Figure 2). Both demonstrate enhanced repellent
Scheme 4. Competing Pathways
Figure 2. Hydrogenation products of (+)-nootkatone.
activity, with respect to their precursor, toward the Formosan
subterranean termite.5 In addition, due to the steric nature
of (+)-nootkatone’s valencane ring system, reactions of 1
often yielded products in an unprecedented high stereose-
lectivity. Those findings will be presented in a subsequent
report.
´
(10) Serebryakov, E. P.; Gamalevich, G. D. IzV. Akad. Nauk, Ser. Khim.
1987, 1, 116–119.
(11) Caine, D.; Chu, C.; Graham, S. L. J. Org. Chem. 1980, 45, 3790–
3797.
(12) Sauer, A. M.; Crowe, W. E.; Laine, R. A.; Henderson, G. An
Efficient and Economic Asymmetric Synthesis of Nootkatone, Tetrahydro-
nootkatone, and Derivatives. Patent Application 11/106,338, filed 2005.
3532
Org. Lett., Vol. 11, No. 16, 2009

Acknowledgment. Support of this work by funds
provided by the USDA/ARS-New Orleans (58-6435-8-
084) and Louisiana State University is gratefully acknowl-
edged. We thank Drs. Dale Treleaven, Frank Zhou and
Mr. Guangyu Li, all of the Department of Chemistry,
Louisiana State University for assistance with 2D NMR
experiments.
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL8023709
Org. Lett., Vol. 11, No. 16, 2009
3533